Editing Bipolar disorder (section)

==Proposed mechanisms==
{{further|Biology of bipolar disorder}}

[[File:Fpsyt-05-00098-g002.jpg|alt=3-D image of human brain emphasizing emotional regulation circuits|thumb|upright=1.6|Brain imaging studies have revealed differences in the volume of various brain regions between patients with bipolar disorder and healthy control subjects.]]

The precise mechanisms that cause bipolar disorder are not well understood. Bipolar disorder is thought to be associated with abnormalities in the structure and function of certain brain areas responsible for cognitive tasks and the processing of emotions.<ref name="Chen2011"/> A neurologic model for bipolar disorder proposes that the emotional circuitry of the brain can be divided into two main parts.<ref name="Chen2011"/> The ventral system (regulates emotional perception) includes brain structures such as the [[amygdala]], [[Insular cortex|insula]], ventral [[striatum]], ventral [[anterior cingulate cortex]], and the [[prefrontal cortex]].<ref name="Chen2011"/> The dorsal system (responsible for emotional regulation) includes the [[hippocampus]], dorsal anterior cingulate cortex, and other parts of the prefrontal cortex.<ref name="Chen2011"/> The model hypothesizes that bipolar disorder may occur when the ventral system is overactivated and the dorsal system is underactivated.<ref name="Chen2011"/> Other models suggest the ability to regulate emotions is disrupted in people with bipolar disorder and that dysfunction of the ventricular prefrontal cortex is crucial to this disruption.<ref name="Chen2011"/>

[[Meta-analysis|Meta-analyses]] of structural [[Magnetic resonance imaging|MRI]] studies have shown that certain brain regions (e.g., the left rostral [[anterior cingulate cortex]], [[insular cortex|fronto-insular cortex]], ventral prefrontal cortex, and [[claustrum]]) are smaller in people with bipolar disorder, whereas other regions are larger ([[lateral ventricles]], [[globus pallidus]], [[Brodmann area 25|subgenual anterior cingulate]], and the amygdala). Additionally, these meta-analyses found that people with bipolar disorder have higher rates of deep [[white matter]] [[hyperintensities]].<ref>{{cite journal | vauthors = Bora E, Fornito A, Yücel M, Pantelis C | title = Voxelwise meta-analysis of gray matter abnormalities in bipolar disorder | journal = Biological Psychiatry | volume = 67 | issue = 11 | pages = 1097–1105 | date = June 2010 | pmid = 20303066 | doi = 10.1016/j.biopsych.2010.01.020 | s2cid = 24812539 }}</ref><ref>{{cite journal | vauthors = Kempton MJ, Geddes JR, Ettinger U, Williams SC, Grasby PM | title = Meta-analysis, database, and meta-regression of 98 structural imaging studies in bipolar disorder | journal = Archives of General Psychiatry | volume = 65 | issue = 9 | pages = 1017–1032 | date = September 2008 | pmid = 18762588 | doi = 10.1001/archpsyc.65.9.1017 | doi-access = free }}</ref><ref name="pmid19721106">{{cite journal | vauthors = Arnone D, Cavanagh J, Gerber D, Lawrie SM, Ebmeier KP, McIntosh AM | title = Magnetic resonance imaging studies in bipolar disorder and schizophrenia: meta-analysis | journal = The British Journal of Psychiatry | volume = 195 | issue = 3 | pages = 194–201 | date = September 2009 | pmid = 19721106 | doi = 10.1192/bjp.bp.108.059717 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Selvaraj S, Arnone D, Job D, Stanfield A, Farrow TF, Nugent AC, Scherk H, Gruber O, Chen X, Sachdev PS, Dickstein DP, Malhi GS, Ha TH, Ha K, Phillips ML, McIntosh AM | title = Grey matter differences in bipolar disorder: a meta-analysis of voxel-based morphometry studies | journal = Bipolar Disorders | volume = 14 | issue = 2 | pages = 135–145 | date = March 2012 | pmid = 22420589 | doi = 10.1111/j.1399-5618.2012.01000.x | s2cid = 2548825 | doi-access = free }}</ref>

[[Functional magnetic resonance imaging|Functional MRI]] findings suggest that the ventricular prefrontal cortex regulates the [[limbic system]], especially the amygdala.<ref name="Strakowski2012"/> In people with bipolar disorder, decreased ventricular prefrontal cortex activity allows for the dysregulated activity of the amygdala, which likely contributes to labile mood and poor emotional regulation.<ref name="Strakowski2012">{{cite journal | vauthors = Strakowski SM, Adler CM, Almeida J, Altshuler LL, Blumberg HP, Chang KD, DelBello MP, Frangou S, McIntosh A, Phillips ML, Sussman JE, Townsend JD | title = The functional neuroanatomy of bipolar disorder: a consensus model | journal = Bipolar Disorders | volume = 14 | issue = 4 | pages = 313–325 | date = June 2012 | pmid = 22631617 | pmc = 3874804 | doi = 10.1111/j.1399-5618.2012.01022.x }}</ref> Consistent with this, pharmacological treatment of mania returns ventricular prefrontal cortex activity to the levels in non-manic people, suggesting that ventricular prefrontal cortex activity is an indicator of mood state. However, while pharmacological treatment of mania reduces amygdala hyperactivity, it remains more active than the amygdala of those without bipolar disorder, suggesting amygdala activity may be a marker of the disorder rather than the current mood state.<ref>{{cite journal | vauthors = Pavuluri M | title = Brain biomarkers of treatment for multi-domain dysfunction: pharmacological FMRI studies in pediatric mania | journal = Neuropsychopharmacology | volume = 40 | issue = 1 | pages = 249–251 | date = January 2015 | pmid = 25482178 | pmc = 4262909 | doi = 10.1038/npp.2014.229 }}</ref> Manic and depressive episodes tend to be characterized by dysfunction in different regions of the ventricular prefrontal cortex. Manic episodes appear to be associated with decreased activation of the right ventricular prefrontal cortex whereas depressive episodes are associated with decreased activation of the left ventricular prefrontal cortex.<ref name="Strakowski2012"/> These disruptions often occur during development linked with [[synaptic pruning]] dysfunction.<ref>{{cite journal | vauthors = Eltokhi A, Janmaat IE, Genedi M, Haarman BC, Sommer IE | title = Dysregulation of synaptic pruning as a possible link between intestinal microbiota dysbiosis and neuropsychiatric disorders | journal = Journal of Neuroscience Research | volume = 98 | issue = 7 | pages = 1335–1369 | date = July 2020 | pmid = 32239720 | doi = 10.1002/jnr.24616 | s2cid = 214772559 | doi-access = free }}</ref>

People with bipolar disorder who are in a [[Euthymia (medicine)|euthymic mood state]] show decreased activity in the [[lingual gyrus]] compared to people without bipolar disorder.<ref name="Chen2011"/> In contrast, they demonstrate decreased activity in the inferior [[frontal cortex]] during manic episodes compared to people without the disorder.<ref name="Chen2011"/> Similar studies examining the differences in brain activity between people with bipolar disorder and those without did not find a consistent area in the brain that was more or less active when comparing these two groups.<ref name="Chen2011">{{cite journal | vauthors = Chen CH, Suckling J, Lennox BR, Ooi C, Bullmore ET | title = A quantitative meta-analysis of fMRI studies in bipolar disorder | journal = Bipolar Disorders | volume = 13 | issue = 1 | pages = 1–15 | date = February 2011 | pmid = 21320248 | doi = 10.1111/j.1399-5618.2011.00893.x }}</ref> People with bipolar have increased activation of left hemisphere ventral limbic areas{{Em dash}}which mediate emotional experiences and generation of emotional responses{{Em dash}}and decreased activation of right hemisphere cortical structures related to cognition{{Em dash}}structures associated with the regulation of emotions.<ref>{{cite journal | vauthors = Houenou J, Frommberger J, Carde S, Glasbrenner M, Diener C, Leboyer M, Wessa M | title = Neuroimaging-based markers of bipolar disorder: evidence from two meta-analyses | journal = Journal of Affective Disorders | volume = 132 | issue = 3 | pages = 344–355 | date = August 2011 | pmid = 21470688 | doi = 10.1016/j.jad.2011.03.016 }}</ref> However, further research is needed to consolidate neuroimaging findings, which are often heterogeneous and not consistently reported according to a common standard.<ref>{{cite journal | vauthors = Merola GP, Tarchi L, Saccaro LF, Delavari F, Piguet C, Van De Ville D, Castellini G, Ricca V | title = Transdiagnostic markers across the psychosis continuum: a systematic review and meta-analysis of resting state fMRI studies | language = English | journal = Frontiers in Psychiatry | volume = 15 | pages = 1378439 | date = 2024-06-04 | pmid = 38895037 | pmc = 11184053 | doi = 10.3389/fpsyt.2024.1378439 | doi-access = free }}</ref>

Neuroscientists have proposed additional models to try to explain the cause of bipolar disorder. One proposed model for bipolar disorder suggests that hypersensitivity of reward circuits consisting of [[frontostriatal circuit]]s causes mania, and decreased sensitivity of these circuits causes depression.<ref>{{cite journal | vauthors = Nusslock R, Young CB, Damme KS | title = Elevated reward-related neural activation as a unique biological marker of bipolar disorder: assessment and treatment implications | journal = Behaviour Research and Therapy | volume = 62 | pages = 74–87 | date = November 2014 | pmid = 25241675 | pmc = 6727647 | doi = 10.1016/j.brat.2014.08.011 }}</ref> According to the "kindling" hypothesis, when people who are genetically predisposed toward bipolar disorder experience stressful events, the stress threshold at which mood changes occur becomes progressively lower, until the episodes eventually start (and recur) spontaneously. There is evidence supporting an association between early-life stress and dysfunction of the [[hypothalamic-pituitary-adrenal axis]] leading to its overactivation, which may play a role in the pathogenesis of bipolar disorder.<ref name="Bender2011">{{cite journal |vauthors=Bender RE, Alloy LB | title = Life stress and kindling in bipolar disorder: review of the evidence and integration with emerging biopsychosocial theories | journal = Clin Psychol Rev | volume = 31 | issue = 3 | pages = 383–398 | date = April 2011 | pmid = 21334286 | pmc = 3072804 | doi = 10.1016/j.cpr.2011.01.004 }}</ref><ref name="Lee2013">{{cite journal |vauthors=Lee HJ, Son GH, Geum D | title = Circadian Rhythm Hypotheses of Mixed Features, Antidepressant Treatment Resistance, and Manic Switching in Bipolar Disorder | journal = Psychiatry Investig | volume = 10 | issue = 3 | pages = 225–232 | date = September 2013 | pmid = 24302944 | pmc = 3843013 | doi=10.4306/pi.2013.10.3.225}}</ref> Other brain components that have been proposed to play a role in bipolar disorder are the [[mitochondria]]<ref name="Nierenberg2013" /> and a sodium [[ATPase]] [[Pump (biochemistry)|pump]].{{sfn|Brown|Basso|2004|p=16}} [[Circadian rhythm]]s and regulation of the hormone [[melatonin]] also seem to be altered.<ref>{{cite journal |vauthors=Dallaspezia S, Benedetti F | title = Melatonin, circadian rhythms, and the clock genes in bipolar disorder | journal = Curr Psychiatry Rep | volume = 11 | issue = 6 | pages = 488–493 | date = December 2009 | pmid = 19909672 | doi=10.1007/s11920-009-0074-1| s2cid = 24799032 }}</ref>

[[Dopamine]], a [[neurotransmitter]] responsible for mood cycling, has increased transmission during the manic phase.<ref name="Salvadore2010" /><ref>{{cite journal |vauthors=Lahera G, Freund N, Sáiz-Ruiz J |title=Salience and dysregulation of the dopaminergic system |journal=Rev Psquiatr Salud Ment |volume=6 |issue=1 |pages=45–51 |date=January–March 2013 |pmid=23084802 |doi=10.1016/j.rpsm.2012.05.003 }}</ref> The dopamine hypothesis states that the increase in dopamine results in secondary [[Homeostasis|homeostatic]] [[Downregulation and upregulation|downregulation]] of key system elements and receptors such as lower sensitivity of dopaminergic receptors. This results in decreased dopamine transmission characteristic of the depressive phase.<ref name="Salvadore2010" /> The depressive phase ends with homeostatic upregulation potentially restarting the cycle over again.<ref>{{cite journal |vauthors=Berk M, Dodd S, Kauer-Sant'anna M, Malhi GS, Bourin M, Kapczinski F, Norman T |title=Dopamine dysregulation syndrome: implications for a dopamine hypothesis of bipolar disorder |journal=Acta Psychiatr Scand Suppl |volume=116 |issue=Supplement s434 |pages=41–49 |year=2007 |pmid=17688462 |doi=10.1111/j.1600-0447.2007.01058.x|s2cid=41155120 }}</ref> [[Glutamate (neurotransmitter)|Glutamate]] is significantly increased within the left dorsolateral prefrontal cortex during the manic phase of bipolar disorder, and returns to normal levels once the phase is over.<ref>{{cite journal |vauthors=Michael N, Erfurth A, Ohrmann P, Gössling M, Arolt V, Heindel W, Pfleiderer B |title=Acute mania is accompanied by elevated glutamate/glutamine levels within the left dorsolateral prefrontal cortex |journal=Psychopharmacology |volume=168 |issue=3 |pages=344–346 |year=2003 |pmid=12684737 |doi=10.1007/s00213-003-1440-z|s2cid=19662149 }}</ref>

Medications used to treat bipolar may exert their effect by modulating intracellular signaling, such as through depleting myo-[[inositol]] levels, inhibition of [[Cyclic AMP|cAMP signaling]], and through altering subunits of the dopamine-associated G-protein.<ref name="Malhi2013">{{cite journal | vauthors = Malhi GS, Tanious M, Das P, Coulston CM, Berk M | title = Potential mechanisms of action of lithium in bipolar disorder. Current understanding | journal = CNS Drugs | volume = 27 | issue = 2 | pages = 135–153 | date = February 2013 | pmid = 23371914 | doi = 10.1007/s40263-013-0039-0 | hdl-access = free | type = Review | s2cid = 26907074 | hdl = 11343/218106 }}</ref> Consistent with this, elevated levels of [[Gi alpha subunit|G<sub>αi</sub>]], [[Gs alpha subunit|G<sub>αs</sub>]], and [[Gq alpha subunit|G<sub>αq/11</sub>]] have been reported in brain and blood samples, along with increased [[protein kinase A]] (PKA) expression and sensitivity;<ref>{{cite book | veditors = Manji HK, Zarate CA | title = Behavioral neurobiology of bipolar disorder and its treatment | url = https://archive.org/details/behavioralneurob00manj | url-access = limited | date = 2011 | publisher = Springer | location = Berlin | isbn = 978-3-642-15756-1 | pages = [https://archive.org/details/behavioralneurob00manj/page/n159 143], 147}}</ref> typically, PKA activates as part of the intracellular signalling cascade downstream from the detachment of G<sub>αs</sub> subunit from the G protein complex.

Decreased levels of [[5-hydroxyindoleacetic acid]], a byproduct of [[serotonin]], are present in the [[cerebrospinal fluid]] of persons with bipolar disorder during both the depressed and manic phases. Increased dopaminergic activity has been hypothesized in manic states due to the ability of [[dopamine]] agonists to stimulate mania in people with bipolar disorder. Decreased sensitivity of regulatory α<sub>2</sub> [[adrenergic receptor]]s as well as increased cell counts in the [[locus coeruleus]] indicated increased noradrenergic activity in manic people. Low plasma GABA levels on both sides of the mood spectrum have been found.<ref>{{cite journal | vauthors = Kapczinski F, Frey BN, Zannatto V | title = [Physiopathology of bipolar disorders: what have changed in the last 10 years?] | journal = Revista Brasileira de Psiquiatria | volume = 26 | issue = Suppl 3 | pages = 17–21 | date = October 2004 | pmid = 15597134 | doi = 10.1590/S1516-44462004000700005 | doi-access = free | hdl = 10183/20098 | hdl-access = free }}</ref> One review found no difference in monoamine levels, but found abnormal norepinephrine turnover in people with bipolar disorder.<ref>{{cite journal | vauthors = Berns GS, Nemeroff CB | title = The neurobiology of bipolar disorder | journal = American Journal of Medical Genetics. Part C, Seminars in Medical Genetics | volume = 123C | issue = 1 | pages = 76–84 | date = November 2003 | pmid = 14601039 | doi = 10.1002/ajmg.c.20016 | citeseerx = 10.1.1.1033.7393 | s2cid = 6550069 }}</ref> [[Tyrosine]] depletion was found to reduce the effects of [[methamphetamine]] in people with bipolar disorder as well as symptoms of mania, implicating dopamine in mania. [[VMAT2]] binding was found to be increased in one study of people with bipolar mania.<ref>{{cite journal | vauthors = Manji HK, Quiroz JA, Payne JL, Singh J, Lopes BP, Viegas JS, Zarate CA | title = The underlying neurobiology of bipolar disorder | journal = World Psychiatry | volume = 2 | issue = 3 | pages = 136–146 | date = October 2003 | pmid = 16946919 | pmc = 1525098 }}</ref>